The pandemic has taken away so many things from so many people. It forced us all to build mutant versions of the ways we live
Alex Zimmer wakes up early when he wants to build a mutant. He needs to get to the lab before the lights come on. The lights are a signal. They tell the fish it’s time to breed.
Zimmer, a post-doctoral fellow at the University of Alberta, studies zebrafish. As creatures, they aren’t much to look at, zebrafish. They’re a few centimetres long. They have tell-tale blue-black and white stripes. But they’re not striking. They don’t jump through any hoops. “They’re just plain fish,” said Marc Ekker, who studies zebrafish at the University of Ottawa. “They’re probably the cheapest fish you can buy.”
What zebrafish do have going for them is that they mature very quickly and they breed in big numbers. A female zebrafish can produce 200 eggs in a week. They’re also cheap to raise and store. And on a genetic level, they’re quite similar to humans.
That’s part of what makes them such ideal candidates for genetic research. On the outside, they’re small and wiggly. They smell like fish. They have gills and little fishy mouths. But strip them down to their genetic architecture and they aren’t that different from you and I.
“Of course, there are sometimes slight differences,” Ekker said. “But very often it’s the same. Nature did not reinvent the wheel many times.”
Zimmer builds zebrafish mutants, turning off their genes one by one, to study the uptake of salt in freshwater fish. Ekker has used them in his lab to isolate genes involved in childhood epilepsy and brain development. Others, all over the world, have used them to study everything from cell regeneration to cancer growth, drug toxicity and novel treatments for rare disease.
Zebrafish are what’s known as a model species. They’re one of four main models geneticists use to map out what role specific genes play in development. “We just want to understand how you build an animal,” said Norbert Perrimon, a professor of genetics at Harvard Medical School.
Most research labs tend to specialize in one species or another. Charles Boone, at the University of Toronto, is a yeast guy. Perrimon focuses on fruit flies. There are fish people. There’s the mouse community. But no matter the species, they’re all doing some variation on the same thing: knocking out genes to find out what they do.
It’s a research principle called “loss of function“ and it underpins almost everything we know about the working lives, mishaps and miracles of genes. “In fact, if loss of function studies did not exist, I don’t know what we would be left with,” Perrimon said.
It’s a simple idea at its core, if one that has had a massive impact on modern science. To find out what something does, you shut it off and see what happens. That’s what makes genetics the closest thing there is to a fairy tale science. It’s all about imagining what life would be like if some tiny part of it were never there.
In flies, you can remove one gene and the wings won’t grow. “You take away another one you may lose the eye,” Perrimon said. Depending on the study, scientists can shut off genes in living models or breed mutants where specific genes never work. They can knock out genes one at a time or in combination. They can program genes to shut down later, once an organism has matured. They can, with incredible precision, target one spot among thousands in a genome and flick it off like a light switch.
If loss of function studies did not exist, I don’t know what we would be left with
That kind of aim wasn’t always possible. The earliest loss of function experiments were more scattershot. They relied on x-rays or chemical mutagens that shut down genes almost at random. Back then, knocking out genes was like shooting a flock of ducks with a shotgun, said Stephanie Mohr, who teaches functional genetics at Harvard. “Eventually over the years, we learned to exercise more and more control,” she said.
Today, most labs work with a technology called CRISPR-Cas9. It acts like a set of genetic scissors, snipping the genome at a precise point and preventing the cell from healing itself. CRISPR has changed everything about gene editing. Today, instead of targeting the whole metaphorical flock, scientists can pick out a single feather on a single duck and pluck it out. “We’re doing stuff we couldn’t even imagine seven years ago,” Boone said. “If God did exist, he would invent this for us.”
Today, thanks to CRISPR, Boone can tell you which genes are essential for yeast to live (about 1,000 of them) and which ones it can survive without (the other 5,000). That ratio holds true for other species too. “A lot of (zebrafish) genes don’t seem to have a particular function,” Zimmer said. “You get rid of (them) and the biological system doesn’t change.”
That applies to humans too. You can shut off thousands of human genes, one at a time, and still have cellular life. Living things, in other words, can survive a tremendous amount of loss.
How that survival happens, though, is its own whole world of inquiry. In some cases, when one gene is shut down, others can compensate, weakening themselves. Other genes, if lost, can cripple or change the organism in grand or tiny ways. Some of the first loss of function experiments were on a fruit fly gene related to eye colour: turn it off, they found, and the fly’s eyes go from red to white. Still other genes, once shut down, remain a mystery. It’s not clear what they did or why. Turn them off and the effect is there, but it remains unknown — a phantom loss that lingers unseen, inside.
I first learned about loss of function two years ago at a lunch at the University of Toronto. I was sitting next to a PhD student who explained her research on the subject to me. I was so struck by the concept that I made a note of it in my phone. “Loss of function: In science you learn what something does by shutting it down.”
I’ve been trying to write about loss of function ever since, but I struggled to find the right way in. It was only recently that it struck me: loss of function is the perfect metaphor for the last six months of our lives.
The COVID-19 pandemic has taken away so many things from so many people. It forced us all to build mutant versions of the ways we live. Through lockdowns and lost friends, closed schools, isolated care homes and lonely deaths, we’ve learned what we can’t survive, what we can and at what cost. You shut things down to find out what they do. And we know now, in a way we never could before, what family means, what human touch, what friendships and jobs and the chance to say goodbye all mean.
You shut things down to find out what they do, and along the way you learn what parts of yourself, and of your world, you need to stay alive.
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World news – CA – In genetics, you shut things down to find out what they do. COVID-19 has done the same to us